Method of treating sexual disturbances

ABSTRACT

The present invention is a method of treating sexual disturbances in humans and inducing mating in non-human mammals using the compounds of formula (A)                    
     in a dosage range where the sexually therapeutic amount is from about 0.2 thru 8 mg/person/dose and where the sexually mating amount is from about 0.003 thru 0.2 mg/kg/dose.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/078,611, filed Feb. 19, 2002, which is in turn a divisional of U.S.patent application Ser. No. 09/465,668, filed Dec. 17, 1999, now U.S.Pat. No. 6,455,564, which claims the benefit of the followingprovisional applications: U.S. Ser. No. 60/120,543, filed Feb. 17, 1999;U.S. Ser. No. 60/115,992 filed Jan. 14, 1999; U.S. Ser. No. 60/115,051,filed Jan. 8, 1999; and U.S. Ser. No. 60/114,840, filed Jan. 6, 1999,under 35 USC §119(e)(1).

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is a method of treating sexual disturbances usingthe compounds of U.S. Pat. No. 5,273,975.

2. Description of the Related Art

There are a number of diseases/conditions which directly affect thesexual lives of humans and animals. These include orgasmic disorders,lack of interest in sex and erectile dysfunction in males. In additionthere are a number of diseases/conditions which indirectly affect thesexual lives of humans. There are a few pharmaceutical agents to treatthis diseases/conditions and others in clinical development.

U.S. Pat. No. 5,273,975 discloses that the compounds (A) of the presentinvention are useful to stimulate sexual activity and to alleviateimpotence. The useful dosage range disclosed in U.S. Pat. No. 5,273,975is “at least 10 mg up to about 1200 mg per day”. The operable dosagerange in the present invention is considerably lower. The compounds ofU.S. Pat. No. 5,273,975 have been used in clinical trials to prove theirusefulness in treating Parkinson's disease at a dose of 30 mg/person.Compounds (A) of the present invention are used at a dose of less than 8mg in treating the sexual disturbances of the present invention. U.S.Pat. No. 5,273,975 generically discloses compounds where the variablesubstituent “A” can be either a carbonyl group (—CO—) or a thiocarbonyl(—CS—).

U.S. Pat. No. 5,250,534 discloses sildenafil (VIAGRA®). The compounds(A) of the present invention are quite different chemically thansildenafil. International Publication WO94/282902 discloses the use ofsildenafil for treating male impotence.

U.S. Pat. No. 4,127,118 discloses the intracavernosal injection of avasodilator for enhancing an erection of the penis. PGE1 is avasodilator and is sold as CAVERJECT® to treat male erectiledysfunction. The compounds (A) of the present invention are notprostaglandins and are not injected into the penis.

International Journal of Impotence Research, 10 (Supplement 3), August1998, Abstracts #417 and 419 disclose that apomorphine, which isavailable in a number of countries to treat Parkinson's Disease, is inlate-stage development as a sublingual formulation for treating maleerectile dysfunction. The compounds (A) used in the present inventionare not apomorphine analogs. U.S. Pat. No. 5,770,606 disclosessublingual use of apomorphine for treating erectile dysfunction.

U.S. Pat. No. 5,541,211 discloses that yohimbine can be used to treaterectile dysfunction. The compounds of formula (A) are quite differentchemically as compared to yohimbine.

U.S. Pat. No. 4,801,587 discloses that phentolamine (VASOMAX®) which isavailable in a number of countries for treating hypertension is alsouseful for treating erectile dysfunction. The compounds of formula (A)are quite different chemically as compared to phentolamine. In addition,the compounds of formula (A) are not applied either topically to thepenis nor intra-urethrally.

U.S. Pat. No. 5,773,020 discloses that intraurethral PGE1 (MUSE) isuseful for treating erectile dysfunction. Compounds (A) are notprostaglandins and are not administered intraurethrally.

Brain Research, 55, 383-389 (1973) reports on the sexually stimulatingeffect of L-DOPA given to male rats and conjuctures that it may be thereason that hypersexuality occasionally is seen in patients withParkinson's syndrome during L-DOPA treatment.

SUMMARY OF INVENTION

Disclosed is a method of treating sexual disturbances in a human who isin need of such treatment which comprises administering a sexuallytherapeutically effective amount of a compound of the formula (A)

where

R₁, R₂ and R₃ are the same or different and are: —H, C₁-C₆ alkyl, C₃-C₅alkenyl, C₃-C₅ alkynyl, C₃-C₅ cycloalkyl, C₄-C₁₀ cycloalkyl, phenylsubstituted C₁-C₆ alkyl, —NR₁R₂ where R₁ and R₂ are cyclized with theattached nitrogen atom to produce pyrrolidiyl, piperidinyl, morphoninyl,4-methyl piperazinyl or imidazolyl;

X is: —H, C₁-C₆ alkyl, —F, —Cl, —Br, —I, —OH, C₁-C₆ alkoxy, cyano,carboxamide, carboxyl, (C₁-C₆ alkoxy)carbonyl;

A is: CH, CH₂, CH-(halogen) where halogen is —F, —Cl, —Br, —I, CHCH₃,C═O, C═S, C—SCH₃, C═NH, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, SO₂, N;

B is: CH₂, CH, CH-(halogen) where halogen is as defined above, C═O, N,NH, N—CH₃,

D is: CH, CH₂, CH-(halogen) where halogen is as defined above, C═O, O,N, NH. N—CH₃, and n is 0 or 1, and where is a single or double bond,with the provisos:

(1) that when n is 0, and

A is CH₂, CH-(halogen) where halogen is as defined above, CHCH₃, C═O,C═S, C═NH, SO_(2,); then

D is CH₂, CH-(halogen) where halogen is as defined above, C═O, O, NH,N—CH₃;

(2) that when n is 0, and

A is CH, C—SCH₃, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, N; then

D is CH, N;

(3) that when n is 1, and

A is CH₂, CH-(halogen) where halogen is as defined above, CHCH₃, C═O,C═S, C═NH, SO₂; and

B is CH₂, CH-(halogen) where halogen is as defined above, C═O, NH,N—CH₃; then

D is CH₂, C═O, O, NH, N—CH₃;

(4) that when n is 1, and

A is CH, C—SCH₃, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, N; and

B is CH, N; then

D is CH₂, C═O, O, NH, N—CH₃;

(5) that when n is 1, and

A is CH₂, CHCH₃, C═O, C═S, C═NH, SO₂, and

B is CH, N; then

D is CH, N; and pharmaceutically acceptable salts thereof to the human.

Also disclosed is a method of inducing mating a non-human mammal whichcomprises administering a sexually mating amount of a compound of theformula (A) and pharmaceutically acceptable salts thereof.

Further disclosed is a method of treating a sexual deficiency state in ahuman who has epilepsy, craniopharyngioma, hypogonadism or who has had ahysterectomyoophorectomy, hysterectomy or oophorectomy which comprisesadministering a sexually therapeutically effective amount of a compoundof the formula (A) and pharmaceutically acceptable salts thereof.

Additionally disclosed is a method of increasing sexual desire, interestor performance in a human who is desirous thereof which comprisesadministering a sexually useful effective amount of a compound of theformula (A) and pharmaceutically acceptable salts thereof.

Disclosed is(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thioneand pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes four separate methods of treating sexualproblems. First, it is a method of treating sexual disturbances in ahuman who is in need of such treatment which comprises administering asexually therapeutic amount of a compound of the formula (A) and itspharmaceutically acceptable salts. Second, it includes a method ofinducing mating a non-human mammal which comprises administering asexually mating amount of a compound of the formula (A) andpharmaceutically acceptable salts thereof. Thirdly, it includes a methodof treating a sexual deficiency state in a human who has adisease/condition the primary pathology of which does not relate tosexual disfunction, but indirectly produces reduced sexual functioning.The diseases/conditions which can produce this type of sexualdisfunction include epilepsy, craniopharyngioma, hypogonadism or who hashad a hysterectomyoophorectomy, hysterectomy or oophorectomy. Fourthly,there are individuals who do not appear to have any sexual disturbanceor disease/condition which will produced an adverse effect on theirsexual lives, but none the less wish to increase their sexual desire,interest or sexual performance and who will benefit by use of thecompounds of formula (A).

The compounds of formula (A), and pharmaceutically acceptable salts,which are useful in the method of treatment of the present invention areknown, see U.S. Pat. No. 5,273,975. It is preferred that thepharmaceutically acceptable salt is selected from the group consistingof salts of the following acids methanesulfonic, hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric,fumaric, maleic, CH₃—(CH₂)_(n)—COOH where n is 0 thru 4,HOOC—(CH₂)_(N)—COOH where n is as defined above. It is preferred thatthe compound of formula (A) have n be 0, A be C═O and D be NH. It ismore preferred that the compound of formula (A) be either(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one or(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione.It is more preferred that the compound of formula (A) be(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1).

A preferred process to produce the preferred compounds within the scopeof the compounds of formula (A) is set forth in PREPARATION 1 and thenumerical EXAMPLEs as well as CHART A.

Non-human mammals include commercial animals (horses, cattle, swine,sheep and transgenic mice) and zoo animals (panda bears, elephants,zebras, lions, tigers, monkeys and apes), sporting animals (horses anddogs) as well as domesticated animals (dogs and cats). The humans andnon-human mammals both be either a male or female.

The sexual disturbances in humans treated by the present inventioninclude hypoactive sexual desire disorder, female sexual arousaldisorder, male erectile disorder, female orgasmic disorder and maleorgasmic disorder. The sexual disturbances of the present invention areknown to those skilled in the art and are adequately described for amedical practitioner. In particular, see Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition, (DSM-IV), AmericanPsychiatric Association, Washington D.C., 1994 as well as the DSM-UVGuidebook, American Psychiatric Press, Inc., Washington D.C., 1995.

When inducing mating in the non-human mammals it is desirable to treatone member of the mating pair in some cases. This is most likely to bethe situation where previous attempts at mating the pair have failed andone member of the pair is not known to have prior offspring. In thatcase, this member would be advantageously treated. In other cases, itmay be desirable to treat both the male and female prior to theanticipated mating. The latter is most likely to be advantageous whenthe intended mating is between sexually inexperienced animals and priorattempts at mating the pair have failed.

The compounds of formula (A) are also useful in treating humans whoseprimary disease, condition or situation is not one of sexualdisfunction, but rather the primary disease or condition leads to asecondary clinical situation where the human (male or female)experiences diminished sexual desire, interest and/or function. Thesediseases include epilepsy, craniopharyngioma, hypogonadism or who hashad a hysterectomyoophorectomy, hysterectomy or oophorectomy and canproduce a sexual deficiency state which is treated in the same way asthose individuals who have one or more of the five sexual disturbancesidentified above. The sexually therapeutic effective amount is the sameand is administered in the same way by the same routes of administrationas for those humans who have sexual disturbances.

The compounds of formula (A) are also useful in increasing sexualdesire, interest or performance in individuals who do not have any ofthe five sexual disturbances nor any of the following diseases orconditions, epilepsy, craniopharyngioma, hypogonadism or who has had ahysterectomyoophorectomy, hysterectomy or oophorectomy. Theseindividuals are treated the same way as those having any of the fivesexual disturbances. The sexually useful effective amount to be usedhere is the same as the sexually therapeutically effective amount forthose with sexual disturbances. The sexually useful therapeuticallyeffective amount is administered in the same way by the same routes ofadministration as for those humans who have sexual disturbances.

In (1) treating the sexual disturbances of humans, (2) inducing matingof non-human mammals, (3) treating humans whose primary disease orcondition leads to a secondary clinical situation where the humanexperiences diminished sexual desire, interest and/or function and (4)increasing the sexual desire, interest or performance in individuals whodo not have any of the above problems the compounds of formula (A) inthe known appropriate pharmaceutical dosage form for a given route ofadministration may be administered orally, intra-nasally, buccally,intra-pulmonary, parenterally and rectally. For treating humans, it ispreferred that the compound of formula (A) be administered orally,intra-nasally, buccally and intra-pulmonarlly; it is more preferred thatthe compounds of formula (A) be administered orally. For treatingnon-human mammals, it is preferred that the compounds of formula (A) beadministered orally, parenterally and rectally; it is more preferredthat the compounds of formula (A) be administered orally.

The operable sexually therapeutic effective amount as well as theoperable sexually useful effective amount of the compounds of formula(A) is from about 0.2 thru about 8 mg/person/dose. It is preferred thatthe sexually therapeutic effective amount and sexually useful effectiveamount is from about 0.5 thru about 5 mg/person/dose. It is morepreferred that the sexually therapeutic effective amount and sexuallyuseful effective amount is from about 1 thru about 3 mg/person/dose. Ifdoses less than this are used the desired effect will not be obtained.If doses greater than this are used, undesirable side effects occur andthe desired effect will not be obtained. The term “therapeutic” is usedin treating a disease or condition; the term “useful” is used whentreating humans who do not have one of the above diseases or conditionswhich cause sexual dysfunction but who are considered normal and whowish to increase their sexual desire, interest or performance.

The operable sexually mating amount of the compounds of formula (A) isfrom about 0.003 thru about 0.2 mg/kg/dose. It is preferred that thesexually mating amount is from about 0.01 thru about 0.125 mg/kg/dose.It is more preferred that the sexually mating amount is from about 0.025thru about 0.075 mg/kg/dose.

To obtain the desired effect in humans, the sexually therapeuticeffective amount or sexually useful effective amount of the compounds offormula (A) should be administered from about 10 minutes to about 8 hrprior to sexual activity. It is preferred that the compounds of formula(A) be administered from about 0.5 hr to about 1 hr prior to sexualactivity. It is more preferred that the compounds of formula (A) beadministered about 0.5 hr prior to sexual activity. Sexual activityincludes sexual intercourse with or without orgasm, ejaculation,masturbation and sexual foreplay.

To obtain the desired mating effect in non-human mammals, the compoundsof formula (A) is administered from about 10 minutes to about 8 hr priorto mating. It is preferred that the compounds of formula (A) beadministered from about 10 minutes to about 1 hr prior to mating. It ismore preferred that the compounds of formula (A) be administered fromabout 10 minutes to about 0.5 hr prior to mating.

It is preferred that the humans do not have Parkinson's disease.

It is preferred that the in humans administration of the compounds offormula (A) does not produce postural hypotension.

The present invention is further illustrated by EXAMPLES A-P.

The exact dosage of the compounds of formula (A) which are useful in thefour methods of this invention depends on the route of administration,the particular compound used, the particular condition being treated,the severity of the condition being treated, the age, weight, generalphysical condition of the particular patient, other medication theindividual may be taking as is well known to those skilled in the artand can be more accurately determined by measuring the blood level orconcentration of the compound and/or metabolite in the patient's bloodand/or the patient's response to the particular condition being treated.

The compounds of formula (A) can also be used with other agents in (1)treating the five sexual disturbances, (2) in inducing mating of anon-human mammal, (3) in treating a sexual deficiency state in humanswho have one or more of the following diseases/conditions—epilepsy,craniopharyngioma, hypogonadism or who has had ahysterectomyoophorectomy, hysterectomy or oophorectomy or (4) increasingsexual desire, interest or performance in a human who does not have anysexual disturbance or one of the above diseases/conditions. It is knownthat vascular smooth muscle relaxation is necessary for vascularengorgement of the penis and the clitoris during normal male and femalesexual behavior and that agents which promote vascular engorgement ofthe penis and clitoris are useful in enhancing sexual motivation, desireand performance. Agents which effectuate vascular smooth musclerelaxation include phosphodiesterase type 5 inhibitors. such assildenafil (Viagra) and ICOS-351; phosphodiesterase type 3 inhibitors,such as milrinone; non-selective phosphodiesterase inhibitors such aspapaverine; nitric oxide donor drugs such as linsidomine; alpha type 1adrenergic receptor antagonists such as phentolamine produce relaxationof vascular smooth muscle from human penis in the presence ofnorepinephrine; alpha type 2 adrenergic receptor antagonists such asyohimbine; prostaglandin E1 receptor agonists such as PGE1 (CAVERJECTT™Injection and MUSE™); as well as vasoactive intestinal polypeptide (VIP)agents.

These vascular smooth muscle relaxation agents are administered by oral,parenteral, buccal, rectal, intranasal, intrapulmonary, intraurethral ortopical routes. The preferred route of administration will depend on thespecific properties of the drug(s) to be combined with the compound(s)of formula (A). The preferred route of administration for aphosphodiesterase type 3 or 5 receptor inhibitor and an alpha type 1 or2 adrenergic receptor inhibitor is oral. The preferred route ofadministration for a prostaglandin E receptor agonist, nitric oxidedonor, non-specific phosphodiesterase inhibitor, and VIP isintracavemosal injection or intraurethral topical administration in malemammals or topical administration to the vulva in the female.

The dose of some of the vascular smooth muscle relaxation agents isknown to those skilled in the art, especially for sildenafil (VIAGRA™Tablets), PGE1 (CAVERJECT™ Injection and MUSE™). For yohimbine the doseis about 1 to about 10 mg orally and can be given about three or fourtimes daily as a routine. For phentolamine the dose is about 2 to about40 mg orally or by bucal patch or about 0.5 to about 5 mg when given byintracavernosal injection. For papaverine the dose is about 4 to about20 mg given by intracavernosal injection. For VIP the dose is about 5 toabout 60 mg when given by intracavernosal injection.

When the compounds of formula (A) are used in conjunction with thevascular smooth muscle relaxation agents the compounds of formula (A)should be administered within the time frame discussed above. Thesexually effective time period for administration of the vascular smoothmuscle relaxation agents is well known for sildenafil (VIAGRA™ Tablets),PGE1 (CAVERJECT™ Injection and MUSE™) The sexually effective time periodfor administration of yohimbine is about 0 to about 4 hours beforesexual activity; for phentolamine it is about 0 to about 4 hours priorto sexual activity when given orally or buccally and about 0 to about 2hours when given by intracaernosal injection; for papaverine and VIP itis about 0 to about 2 hours prior to sexual activity.

When used in combination, the preferred combinations are(5R)-(methylamino)- 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneand sildenafil,(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneand PGE1,(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thioneand sildenafil or(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thioneand PGE1.

Definitions and Conventions

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

I. Conventions for Formulas and Definitions of Variables

The carbon atom content of variable substituents is indicated in one oftwo ways. The first method uses a prefix to the entire name of thevariable such as “C₁-C₄”, where both “1” and “4” are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variable by a space. Forexample, “C₁-C₄ alkyl” represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Whenever this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂-C₄ alkoxycarbonyl describes a group CH₃—(CH₂)_(n)—O—CO— where nis zero, one or two. By the second method the carbon atom content ofonly each portion of the definition is indicated separately by enclosingthe “C_(i)-C_(j)” designation in parentheses and placing it immediately(no intervening space) before the portion of the definition beingdefined. By this optional convention (C₁-C₃)alkoxycarbonyl has the samemeaning as C₂-C₄ alkoxycarbonyl because the “C₁-C₃” refers only to thecarbon atom content of the alkoxy group. Similarly while both C₂-C₆alkoxyalkyl and (C₁-C₃)alkoxy(C₁-C₃)alkyl) define alkoxyalkyl groupscontaining from 2 to 6 carbon atoms, the two definitions differ sincethe former definition allows either the alkoxy or alkyl portion alone tocontain 4 or 5 carbon atoms while the latter definition limits either ofthese groups to 3 carbon atoms.

II. Definitions

All temperatures are in degrees Centigrade.

TLC refers to thin-layer chromatography.

HPLC refers to high pressure liquid chromatography.

Saline refers to an aqueous saturated sodium chloride solution.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) downfield from tetramethylsilane.

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts arereported in ppm (δ) downfield from TMS.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysicauchemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

Pharmaceutically acceptable anion salts include salts of the followingacids methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric,nitric, benzoic, citric, tartaric, fumaric, maleic, CH₃—(CH₂)_(n)—COOHwhere n is 0 thru 4, HOOC—(CH₂)_(N)—COOH where n is as defined above.

(Z)-2-butenedioate refers to maleate.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

Sexual disturbance refers to hypoactive sexual desire disorder, femalesexual arousal disorder, male erectile disorder, female orgasmicdisorder, and male orgasmic disorder as defined in Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, (DSM-IV),American Psychiatric Association, Washington D.C., 1994 as well as theDSM-IV Guidebook, American Psychiatric Press, Inc., Washington D.C.,1995. These definitions of the particular disease states are as theywere defined in 1994 and 1995. The five “sexual disturbances” are stilldefined the same today. In the future, the terms for these sexualdisturbances may change, but one skilled in the art will know andrealize the disease states themselves are the same.

Sexual activity includes sexual intercourse with or without orgasm,ejaculation, masturbation and sexual foreplay.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

Preparation 1 (R)-Naproxen Chloride

R-naproxen (260 g), methylene chloride (3.33 kg) and DMF (8.2 ml) areadded to a reactor. Oxalyl chloride (191.8 g) is slowly added to thismixture. After addition of the oxalyl chloride, the slurry is stirred at5 to 10° and then slowly warmed to 20-25°. The resulting mixture isconcentrated to remove the methylene chloride, branched octane is addedto the concentrate and the mixture is again concentrated. More branchedoctane is added to the concentrate and the mixture is cooled to 0° andstirred to crystallize. The crystal slurry is filtered, the crystal cakeis washed with octane and dried at 20-25° to obtain the title compound.

The filtrate from the first crop is concentrated, branched octane isadded and the mixture is cooled and stirred to obtain a second crop ofthe title compound. The slurry is filtered, the crystal cake is washedwith branched octane and dried at 20-25°.

Example 1 1-Benzyl-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (II)

A mixture of 4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (I, J. HeterocyclicChem., 19, 837-49 (1982), 1.0 g, 5.8 mmol) in DMF (10 ml) is cooled to0° and treated with potassium t-butoxide in THF (1.98 M, 3.2 ml, 6.3mmol) maintaining the reaction temperature at 0°. The resulting mixtureis stirred at 0° for 10 minutes. Benzyl bromide (0.73 ml, 6.1 mmol) isthen added while maintaining the reaction temperature at 0°. After 1 hr,the mixture is partitioned with methyl t-butyl ether (MTBE) from waterfollowed by several water washes. The MTBE phase is concentrated underreduced pressure. The concentrate is cooled to 0°, filtered and washedtwo times with 0° MTBE. The product is dried at 50° under reducedpressure with a nitrogen purge to give the title compound, CMR (CDCl₃,100 MHz) L 153.78, 136.44, 128.69, 127.67, 127.60, 126.73, 125.86,122.90, 122.78, 121.28, 116.92, 116.17, 108.36, 44.95 and 42.37.

Example 2(5R*,6R*)-1-benzyl-5-bromo-6-hydroxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(III)

1-Benzyl-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (II, XAMPLE 1, 240 g),acetonitrile (1.086 kg), water (227 ml) and fluoboric acid (48.5%, 13.4g) are mixed and cooled to 0 to 5°. Dibromantin (163.5 g) is slurriedinto acetonitrile and is added to the reaction mixture. The reaction iscarried out for about 3 hr at 0 to 5°. After the reaction is complete,methyl t-butyl ether is added over about 45 minutes keeping the reactiontemperature in the pot below 10°. The slurry is cooled to −10 to −15°,stirred for an hour and then filtered. The product is washed withprecooled methyl t-butyl ether, dried with 40° nitrogen to give thetitle compound. CMR (CDCl₃) δ156.0, 137.8, 130.5, 129.6, 129.3, 129.1,126.6, 123.6, 122.5, 119.6, 110.4, 69.9, 49.6, 47.7, 46.9 and 43.8.

Example 3(5S,6S)-1-Benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl(2R)-2-(6-methoxy-2-naphthyl)propanoate (WA) and(5R,6R)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl(2R)-2-(6-methoxy-2-naphthyl)propanoate (IVB)

(5R,6R)-1-Benzyl-5-bromo-6-hydroxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(III, EXAMPLE 2, 143 g), methylene chloride (3,136 g), N-methylmorpholine (100.2 g) and 4-dimethylaminopyridine (497 mg) are added tothe reactor and the mixture is cooled to 0 to 5°. (R)-Naproxen chloride(PREPARATION 1, 118.5 g) dissolved in methylene chloride (694 ml) isadded to the reactor over about 1 hr and the mixture is stirred at 0 to5° to complete the reaction. If necessary, additional naproxen chlorideis added to complete the reaction. Potassium carbonate solution dilutedwith water is added to the mixture. The aqueous phase is extracted withmethylene chloride and the combined methylene phase is washed withwater. The washed mixture is concentrated by vacuum distillation andsolvent exchange with ethyl acetate is performed. The concentrate iscooled to −10° and stirred. The crystal slurry is filtered and thecrystal cake is washed with precooled methyl t-butyl ether and dried at50° to give the title compound in solid form,(5S,6S)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl(2R)-2-(6-methoxy-2-naphthyl)propanoate (IVA), CMR (CDCl₃) δ173.2,157.8, 153.4, 136.1, 134.6, 133.7, 129.2, 128.8, 127.8, 127.8, 127.6,127.2, 125.9, 125.9, 125.6, 121.5, 121.4, 119.1, 113.2, 109.0, 105,105.6, 69.2, 55.3, 45.4, 45.2, 42.5, 41.7 and 18.3.

The undesired isomer,(5R,6R)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl(2R)-2-(6-methoxy-2-naphthyl)propanoate (IVB) is in the filtrate and canbe recovered by means well known to those skilled in the art,(5R,6R)-1-benzyl-5-hydroxy-6-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one,CMR 173.2, 157.9, 153.4, 136.1, 135.0, 133.8, 129.2, 128.9, 128.8,127.8, 127.6, 127.4, 125.8, 125.8, 125.7, 121.6, 121.5, 119.3, 113.1,109.1, 105.7, 68.7, 55.3, 45.3, 45.2, 42.2, 41.3 and 18.1 δ.

Example 4(5R,6R)-1-benzyl-5-hydroxy-6-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(V)

(5S,6S)-1-Benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl(2R)-2-(6-methoxy-2-naphthyl)propanoate (IVA, EXAMPLE 3, 110 g) isslurried in acetonitrile (1,297 g). After adding aqueous methylamine (40wt %, 327 g) the reaction is carried out for about 12 hr at about 30°.After the reaction is complete, the mixture is concentrated and ethylacetate is added. Dilute hydrochloric acid is added to make thewater-soluble salt of the title compound. The byproduct (R-naproxenacetamide impurity) is insoluble in water and stays in the ethyl acetatephase. Further extractions and washes are carried out for betterseparation of the (naproxen acetamide) impurity with minimum loss of thedesired product. Then a sodium hydroxide solution is added to theaqueous phase and the hydrochloride salt of the title compound isconverted to the free base. The free base is less soluble in water andis extracted into ethyl acetate. The product mixture is concentrated andsolvent exchanged with ethyl acetate to remove water. Crystallization isperformed by adding branched chain octane and cooling the mixture. Theresulting slurry is filtered, washed and dried at 50° to give the titlecompound, CMR (CDCl₃) δ153.7, 136.3, 128.7, 127.8, 127.7, 125.7, 121.3,119.9, 118.6, 107.5, 66.2, 60.1, 45.1, 42.6 and 34.0.

Example 5(7aS,8aR)-4-benzyl-8-methyl-7,7a,8,8a-tetrahydroazireno[2,3-c]imidazo[4,5,1-ij]quinolin-5(4H)-one(VI)

(5R,6R)-1-benzyl-5-hydroxy-6-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(V, EXAMPLE 4, 70 g) and THF (1,389 g) is concentrated to remove anymoisture with distillate as a precaution due to reactivity of n-butyllithium towards water. The mixture is cooled to about −10° andn-butyllithium is added to make the lithium salt of the startingmaterial with formation of n-butane byproduct in an exothermic reaction.Benzene sulfonyl chloride is added slowly to make benzene sulfonate inan exothermic reaction. The reaction mixture is warmed to 20-25° tocomplete the reaction. Agueous potassium carbonate solution is added toscavenge the benzene sulfonic acid and the mixture is stirred to allowcrystallization. Water is added to complete crystallization, the slurryis stirred, cooled and filtered. The crystal cake is washed with waterfollowed by branched chain octane and dried at 40 to 50° to give thetitle compound, CMR (CDCl₃) δ154.1, 136.3, 128.6, 127.9, 127.6, 124.3,120.7, 119.7, 107.4, 46.7, 44.9. 40.7, 38.1 and 37.6.

Example 6(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(VII)

A mixture of(7aS,8aR)-4-benzyl-8-methyl-7,7a,8,8a-tetrahydroazireno[2,3-c]imidazo[4,5,1-ij]quinolin-5(4H)-one(VI, EXAMPLE 5, 40 g) t-amyl alcohol (42.4 g) and anhydrous ammonia(1,200 g) is treated with lithium at −33°. After the lithium addition iscomplete, the reaction mixture changes from a yellow slurry to a darkblue mixture. This dark blue mixture is stirred for 30-60 minutes andthen quenched with the addition of water. The cooling is removed fromthe condenser and the ammonia is allowed to evaporate. The residue isdissolved in methanol. This mixture is then concentrated to dryness togive the title compound, which is carried on directly to the next stepwithout isolation.

Example 7(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) (VIE)

(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(VII, EXAMPLE 6, 28.0 g) is dissolved in water and the pH is adjusted to10 with the addition of hydrochloric acid. The mixture is applied inportions to an XAD-16 resin column which is eluted first with water andthen with ethanol. The inorganic salts are eluted from the column firstwith the desired product eluted with the ethanol. The ethanol eluatefrom the column is treated with maleic acid and the water level islowered through azeotropic distillation of the ethanol. The precipitatedproduct is isolated by filtration, rinsed with ethyl acetate and driedto give the title compound, CMR (DMSO-d₆) δ167.6, 153.9, 136.4, 127.1,121.5, 119.6, 114.1, 107.5, 51.9, 31.3 and 26.5.

Example 8(5R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione

A mixture of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(VII, EXAMPLE 6, 15.0 g, 73.8 mmol) and tetraphosphorus decasulfide(36.1 g, 81.2 mmol) in pyridine (300 mL) is heated in a 125° oil bathunder nitrogen. The reaction is stirred for 5 hr. The mixture is cooledto 20-25° and the pyridine is removed under reduced pressure. Sodiumhydroxide (2.2 N, 200 mL) is added. Sodium hydroxide (1 N) is thenadded. The mixture is saturated with sodium chloride and extracted withmethylene chloride (2.5 L, in portions). The organic phase is absorbedonto silica gel (40 g) and purified via column chromatography (silicagel; 225 g; methanol/methylene chloride, 3.5-5.0/96.5-95) to give asolid. Recrystallization of this material from methanol/ethylacetate/hexanes give the title compound, mp=210-213°; IR (drift) 2940,2907, 2884, 1483, 1458, 1391, 1366, 1354, 1254, 1239, 1229, 895, 762,734, 630 cm⁻¹; NMR (300 MHz, CDCl₃) 7.12, 7.03, 7.00, 4.30, 3.96,3.30-3.50, 3.15, 2.88 and 2.57 δ; MS (EI, m/z) 219 (M⁺), 190, 189, 187,186, 164, 163, 155, 145; HRMS (FAB) calculated for C, H₁₃N₃S(MH⁺)=220.0908, found 220.0904.

Example 9(5R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionemalate

A mixture of maleic acid (0.317 g, 2.36 mmol) in a minimal amount ofmethanol (˜1 mL) is added to a mixture of(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione(EXAMPLE 8, 0.493 g, 2.25 mmol) in methylene chloride. The resultingsolid is collected by filtration to give the title compound,mp=195-196°; [α]²⁵ _(D)=−60° (c 0.93, methanol); IR (drift) 3140, 3112,3060, 2969, 1627, 1619, 1568, 1481, 1455, 1398, 1389, 1361, 1220, 868and 747 cm⁻¹; NMR (300 MHz, CD₃OD) 7.20-7.30, 7.10-7.20, 6.26, 4.49,4.31, 4.05-4.20, 3.47, 3.28 and 2.83 δ; CMR (100 MHz, DMSO-d₆+CD₃OD)170.4, 169.4, 136.6, 131.1, 130.9, 125.1, 122.1, 116.2, 109.6, 53.9,43.1, 31.9 and 27.2 δ; MS (ESI, m/z) 220.1 (MH⁺).

Example A Hypoactive Sexual Desire Disorder in a Female Patient

A 44 kg, 24 year old female patient is referred by her psychologist forevaluation for and medical treatment of hypoactive sexual desiredisorder. The patient recently began to co-habitate with a 28 year oldman. She consulted a clinical psychologist because of distress overfrequent arguments with her partner. These arguments concern herfrustration that her partner is unwilling to marry her and the partner'saccusations that she is sexually unresponsive and “boring in bed.” Thepatient reports that although she desires to continue the relationship,she has little or no interest in sexual activity with this partner. Thepartner initiates all sexual activity in the relationship and shecomplies so that the relationship will continue. She states that herpartner desires sexual intercourse about once per day. Occasionally, thecouple's frequency of sexual intercourse is as much as twice per day.She reports that she does not have sexual fantasies since the presentrelationship began. The patient had a previous relationship with a manthat lasted 3 years and involved sexual activity that she found sexuallyexciting and satisfying. The patient has recently had a physicalexamination by her family physician, the findings of which wereunremarkable. She currently takes no prescription drugs other than lowdose birth control pills. She does not routinely use over-the-countermedications or alcohol and denies taking drugs of abuse. The patient isdiagnosed as having Hypoactive Sexual Desire Disorder of acquired onsetdue to situational factor (Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition, 1994).(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) is prescribed at 1 mg/dose to be taken 0.5 hrbefore the patient intends to engage in sexual activity. The patient isinstructed that she may use the drug on a daily basis, if she and herpartner desire sexual activity at this frequency. She is also instructedthat on occasions she may use the drug twice in a single day if this isthe intended frequency of intercourse. The patient is examined after onemonth. She reports that she uses the drug once, and occasionally twice,per day. She reports that she has sexual fantasies on 3-4 occasions perweek, occasionally initiates sexual activity with her partner, andenjoys an improved sexual relationship with her partner. She alsoreports that she and her partner argue less frequently and that herpartner no longer accuses her of being disinterested in sexualrelations. The patient is instructed to continue using the drug.

Example B Female Sexual Arousal Disorder In A Female Patient

A 64 kg, 22 year old female patient is complaining of vaginal drynessand mild discomfort during sexual intercourse. The patient recentlybegan a relationship with a 35 year old man. Her partner complained ofher vaginal dryness and poor vaginal expansion during sexualintercourse. Her partner has made several comments about this during theprevious two months and the patient is concerned that her partner isdissatisfied with her lack of sexual responsiveness and may end therelationship. The patient reports that she desires to continue therelationship. The patient has had several previous sexual relationships.She reports that vaginal dryness and some discomfort with vaginalintercourse has occurred during her past sexual relationships. Onquestioning, she indicates that she has little or no sense of sexualarousal during intercourse. The patient indicates that she has sexualfantasies several times per week. She finds her current partnerattractive and sexual desirable. She indicates that she masturbatesapproximately once per week. During these episodes she usually has anorgasm. Lubrication is not a problem when she masturbates. The patienthas recently had a physical examination by her family physician, thefindings of which were unremarkable. She currently takes no prescriptiondrugs other than low dose birth control pills. She does not routinelyuse over-the-counter medications or alcohol and denies taking drugs ofabuse. The patient is diagnosed as having Female Sexual Arousal Disorderthat is situational due to psychological factors (Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, 1994).(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) is prescribed at 3 mg/dose to be taken 0.5-1 hrbefore the patient intends to engage in sexual activity. The patient isinstructed that she may use the drug on a daily basis, if this is theintended frequency of sexual activity. The patient is examined after onemonth. She reports that she uses the drug prior to intercourse. Shereports that vaginal dryness is no longer a problem and that she nolonger has pain during initiation of vaginal penetration by her partner.She enjoys an improved sexual relationship with her partner. The patientis instructed to continue using the drug.

Example C Male Erectile Disorder

A 75 kg, 56 year old male patient has been married for 20 years. Hepresents complaining that for the past six months he has had difficultymaintaining an erection until completion of sexual intercourse. Hedevelops an adequate erection at the beginning of sexual activity butdetumescence occurs when he attempts penetration. His wife is his onlycurrent sexual partner. He reports that his wife is patient andunderstanding of his problem but that he is embarrassed, feels that heis a failure, and is growing progressively more angry and sad about hisinability to maintain an erection. He masturbates approximately twiceeach month. During masturbation, he is usually able to maintain anerection until he ejaculates. The patient has recently had a physicalexamination by his family physician. The only remarkable findings were asupine diastolic blood pressure 94 mm mercury and a total plasmacholesterol level of 230 mg/dl. He was instructed to follow the AmericanHeart Association dietary recommendations and to reduce his body weightby 5 kg. He currently takes no prescription drugs. He does not routinelyuse over-the-counter medications or alcohol and denies taking drugs ofabuse. The patient is diagnosed as having Male Erectile Disorder that isacquired and situational. The etiology is most likely due topsychological factors, although combined factors, e.g., mildhypertension or atherosclerosis, may contribute (Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, 1994).(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) is prescribed at 3 mg/dose to be taken 0.5 hrbefore the patient intends to engage in sexual activity. The patient isinstructed that he may use the drug on a daily basis, if this is theintended frequency of sexual activity. The patient is examined after onemonth. He reports that he uses the drug prior to intercourse. He reportsthat he maintains an erection for a satisfactory period after vaginalpenetration in almost every attempt at intercourse. He usuallyexperiences intra-vaginal ejaculation. The patient and his wife considerthe quality of their sexual relationship to be markedly improved. Thepatient is instructed to continue using the drug.

Example D Female Orgasmic Disorder

A 50 kg, 22 year old female patient who married three months beforepresenting for treatment. She complains that she does not have an orgasmduring sexual activity with her husband even though she enjoy theexperience and become sexually excited during intercourse. She was notsexually active prior to marriage. She reports that her husband hadmultiple premarital partners and that he reports all his past partnershad orgasms. The patient is upset by her inability to have orgasms andfeels she is an poor wife. On questioning she reports that she is “toofat” although her weight is appropriate for her height. She does notmasturbate. The patient has recently had a physical examination by herfamily physician, the findings of which were unremarkable. She currentlytakes no prescription drugs other than low dose birth control pills. Shedoes not routinely use over-the-counter medications or alcohol anddenies taking drugs of abuse. The patient is diagnosed as having FemaleOrgasmic Disorder that is situational due to psychological factors(Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,1994).(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) is prescribed at 1 mg/dose to be taken about0.5 hr before the patient intends to engage in sexual activity. Thepatient is instructed that she may use the drug on a daily basis, ifthis is the intended frequency of sexual activity. The patient isexamined after two months. She reports that she uses the drug prior tointercourse. She reports that she has an orgasm during sexualintercourse on most occasions. She enjoys an improved sexualrelationship with her partner. It is recommended that the patientcontinue to use the drug for an additional six months, then stop takingthe drug for a period of two weeks to determine whether she might now beable to have orgasms in the absence of drug therapy.

Example E Male Orgasmic Disorder

A 80 kg, 40 year old man has been married for 15 years. He presentscomplaining that he has begun to have difficulty achieving an orgasmduring vaginal intercourse with his wife. On most occasions he is unableto ejaculate during sexual intercourse. Infrequently, he is able toejaculate during sexual, but only after very prolonged vaginalintercourse. He indicates that this has been occurring for at leastthree months and that he is frustrated and angry about the situation.His further reports that his wife finds the prolonged intercourse thathe requires to ejaculate uncomfortable and has begun avoiding sexualrelations. He reports that he ejaculate normally when he masturbates.The patient has recently had a physical examination by his familyphysician, the findings of which were unremarkable. He currently takesno prescription drugs. He does not routinely use over-the-countermedications or alcohol and denies taking drugs of abuse. The patient isdiagnosed as having Male Orgasmic Disorder that is acquired andsituational due to psychological factors (Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition, 1994). (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Z)-2-butenedioate(1:1) is prescribed at 3 mg/dose to be taken 0.5-1 hr before the patientintends to engage in sexual activity. The patient is instructed that hemay use the drug on a daily basis, if this is the intended frequency ofsexual activity. The patient is examined after one month. At this visithe reports that he now ejaculates during vaginal intercourse on alloccasions. The patient and his wife consider the quality of their sexualrelationship to be markedly improved. The patient is instructed tocontinue using the drug.

Example F Mating of Animals of Commercial Value

An adult male Giant Panda on temporary loan from a foreign zoo isdesired to have breed to an adult female Giant Panda which is normallyresident at the zoo. Because of the commercial value of a potentialoff-spring it is desirable that the animals mate during the time theadult male is on loan. Both animals are sexually inexperienced and donot engage in intercourse during a two week period. As an alternative toanesthetizing the animals for a facilitated transfer of semen betweenthe animals, the male and female Giant Pandas have(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (II) added to their diet on one occasion. Theconcentration of drug in the diet is calculated to deliver 0.05 mg offree base equivalents of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) per kilogram of body weight. One hour afteringesting the diet containing drug, the animals engage in sexualintercourse. A pregnancy and subsequent birth of an off-spring resultsfrom this intercourse.

Example G Reduced Sexual Function in a Male With Idiopathic Epilepsy

A 40 year old, 75 kg male patient has idiopathic epilepsy. He firstpresented with primary generalized seizures at age 15 years and wasdiagnosed with idiopathic epilepsy. He has been treated withcarbamazepine since age 20. Currently he receives 500 mg/day of thedrug. He has had two tonic-clonic seizures during the preceding year.The patient complains of diminished sexual interest in his wife of 8years. On those occasions when he attempts sexual intercourse, he isable to maintain an erection sufficient for intercourse one-third of thetime. He indicates that this problem has had a gradual onset over theprevious 5 years. He reports that he rarely has sexual fantasies andrarely masturbates. The patient has recently had a physical examinationby his family physician, the findings of which were unremarkable. Hecurrently takes no prescription drugs other than carbamazepine. He doesnot routinely use over-the-counter medications or alcohol and deniestaking drugs of abuse. A penile injection test with Caverject™ Injectionresults in a normal erection and duplex Doppler ultrasonographyindicates an intact vascular system. Plasma testosterone and sex hormonebinding globulin assays are performed. The plasma testosterone level is25 nM, which is considered normal. The plasma sex hormone bindingglobulin level is 55 nM, which is considered elevated compared to thenormal range. The patient is diagnosed with hypogonadism, secondary tochronic carbamazepine treatment (Epilepsia 36: 366-370, 1995).(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) is prescribed at 3 mg/dose to be taken 0.5 hrbefore the patient intends to engage in sexual activity. The patient isinstructed that he may use the drug on a daily basis, if this is theintended frequency of sexual activity. The patient is examined after onemonth. He reports that he take the drug 2-3 times per week. After takingthe drug, he feels more interest in sex and usually initiates sexualactivity with his wife. He reports that enjoys a normal sexualrelationship. The patient is instructed to continue with the treatment.

Example H Reduced Sexual Function in a Male Patient with ErectileDysfunction and Hypoactive Sexual Desire Disorder

A 55 year old, 70 kg, male patient is apparently in good health. Hepresents complaining of a loss of sexual desire and frequent erectiledysfunction since taking an executive position in his company, six weekspreviously. He reports that he works long hours and feels a high degreeof pressure associated with his job. He is frustrated and angry thatwhen he takes time off from work he is unable to have an intimaterelationship with his wife. He reports that although he is periodicallyinterested in initiating sexual relations, on most occasions he isunable to maintain a high level of interest sufficiently long toinitiate or to adequately respond to his wife's initiating sexualactivity. He further indicates that for the past six months, he has haddifficulty maintaining an erection until completion of sexualintercourse. He develops a semi-rigid erection at the beginning ofsexual activity but detumescence occurs when he attempts penetration. Hereports that he has few erotic fantasies. He has not masturbated for thepast several months. He attributes this to a lack of motivation andinterest. The patient has recently had a physical examination by hisfamily physician, the findings of which were unremarkable. He does notroutinely use over-the-counter medications or alcohol and denies takingdrugs of abuse.(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1), 3 mg/dose, and sildenafil (VIAGRA Tablets), 50mg/dose, are both prescribed. Each is to be taken orally about 0.5 hrbefore the patient intends to engage in sexual activity. The patient isinstructed that he may use the drug combination on a daily basis, ifthis is the intended frequency of sexual activity. The patient isexamined after one month. He reports that he takes the drug combination2-3 times per week. After taking the drug combination he feels motivatedto initiate sexual activity, readily has sexual fantasies that aresustained during sexual intercourse, and has no difficulty maintainingan erection to completion of sexual intercourse. He reports that heenjoys an improved sexual relationship with his partner. The patient isadvised to continue taking the(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) for another six months as he adapts to thesituational stress associated with his new job. After this time he isadvised to stop taking the drug for a period of two weeks to determinewhether his sexual motivation and desire have returned to the level heenjoyed prior to the change in jobs.

Example I Hypoactive Sexual Desire Disorder in a Female Patient

Following the general method of treatment of EXAMPLE A and makingnon-critical variations but using(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionein place of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) the same positive treatment effect is obtained.

Example J Female Sexual Arousal Disorder in a Female Patient

Following the general method of treatment of EXAMPLE B and makingnon-critical variations but using(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionein place of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) the same positive treatment effect is obtained.

Example K Male Erectile Disorder

Following the general method of treatment of EXAMPLE C and makingnon-critical variations but using(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionein place of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) the same positive treatment effect is obtained.

Example L Female Orgasmic Disorder

Following the general method of treatment of EXAMPLE D and makingnon-critical variations but using(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionein place of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) the same positive treatment effect is obtained.

Example M Male Orgasmic Disorder

Following the general method of treatment of EXAMPLE E and makingnon-critical variations but using(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionein place of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) the same positive treatment effect is obtained.

Example N Mating of Animals of Commercial Value

Following the general method of treatment of EXAMPLE F and makingnon-critical variations but using(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionein place of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) the same positive treatment effect is obtained.

Example O Reduced Sexual Function in a Male with Idiopathic Epilepsy

Following the general method of treatment of EXAMPLE G and makingnon-critical variations but using(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionein place of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) the same positive treatment effect is obtained.

Example P Reduced Sexual Function in a Male Patient with ErectileDysfunction and Hypoactive Sexual Desire Disorder

Following the general method of treatment of EXAMPLE H and makingnon-critical variations but using(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionein place of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1) the same positive treatment effect is obtained.

Enumerated Embodiments of the Invention

1. A method of treating sexual disturbances in a human who is in need ofsuch treatment which comprises administering a sexually therapeuticallyeffective amount of a compound of the formula (A)

where

R₁, R₂ and R₃ are the same or different and are:

—H,

C₁-C₆ alkyl,

C₃-C₅ alkenyl,

C₃-C₅ alkynyl,

C₃-C₅ cycloalkyl,

C₄-C₁₀ cycloalkyl,

phenyl substituted C₁-C₆ alkyl,

—NR₁R₂ where R₁ and R₂ are cyclized with the attached nitrogen atom toproduce pyrrolidiyl, piperidinyl, morphoninyl, 4-methyl piperazinyl orimidazolyl;

X is:

—H,

C₁-C₆ alkyl,

—F, —Cl, —Br, —I,

—OH,

C₁-C₆ alkoxy,

cyano,

carboxamide,

carboxyl,

(C₁-C₆ alkoxy)carbonyl,

A is:

CH,

CH₂,

CH-(halogen) where halogen is —F, —Cl, —Br, —I,

CHCH₃,

C═O,

C═S,

C—SCH₃,

C═NH,

C—NH₂,

C—NHCH₃,

C—NHCOOCH₃,

C—NHCN,

SO₂,

N;

B is:

CH₂,

CH,

CH-(halogen) where halogen is as defined above,

C═O,

N,

NH,

N—CH₃,

D is:

CH,

CH₂,

CH-(halogen) where halogen is as defined above,

C═O,

O,

N,

NH,

N—CH₃,

and n is 0 or 1, and where is a single or double bond, with theprovisos:

(1) that when n is 0, and

A is CH₂, CH-(halogen) where halogen is as defined above, CHCH₃, C═O,C═S, C═NH, SO₂,

then D is CH₂, CH-(halogen) where halogen is as defined above. C═O, O,NH, N—CH₃,

(2) that when n is 0, and

A is CH, C—SCH₃, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, N; then

D is CH, N

(3) that when n is 1, and

A is CH₂, CH-(halogen) where halogen is as defined above, CHCH₃, C═O,C═S, C═NH, SO₂; and

B is CH₂, CH-(halogen) where halogen is as defined above, C═O, NH,N—CH₃; then

D is CH₂, C═O, O, NH, N—CH₃,

(4) that when n is 1, and

A is CH, C—SCH₃, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, N; and

B is CH, N; then

D is CH₂, C═O, O, NH, N—CH₃,

(5) that when n is 1, and

A is CH₂, CHCH₃, C═O, C—S, C═NH, SO₂, and

B is CH, N; then

D is CH, N; and pharmaceutically acceptable salts thereof to the human.

2. A method of treating sexual disturbances according to enumeratedembodiment 1 where the mammal is a male.

3. A method of treating sexual disturbances according to enumeratedembodiment 1 where the mammal is a female.

4. A method of treating sexual disturbances according to enumeratedembodiment 1 where the sexual disturbance is selected from the groupconsisting of hypoactive sexual desire disorder, female sexual arousaldisorder, male erectile disorder, female orgasmic disorder, and maleorgasmic disorder.

5. A method of treating sexual disturbances according to enumeratedembodiment 4 where the sexual disturbance is hypoactive sexual desiredisorder.

6. A method of treating sexual disturbances according to enumeratedembodiment 4 where the sexual disturbance is female sexual arousaldisorder.

7. A method of treating sexual disturbances according to enumeratedembodiment 4 where the sexual disturbance is male erectile disorder.

8. A method of treating sexual disturbances according to enumeratedembodiment 4 where the sexual disturbance is female orgasmic disorder.

9. A method of treating sexual disturbances according to enumeratedembodiment 4 where the sexual disturbance is male orgasmic disorder.

10. A method of treating sexual disturbances according to enumeratedembodiment 1 where the compound of formula (A) is administered orally,intra-nasally, buccally, intra-pulmonary, parenterally and rectally.

11. A method of treating sexual disturbances according to enumeratedembodiment 10 where the compound of formula (A) is administered orally,intra-nasally, buccally and intra-pulmonary.

12. A method of treating sexual disturbances according to enumeratedembodiment 10 where the compound of formula (A) is administered orally.

13. A method of treating sexual disturbances according to enumeratedembodiment 1 where the sexually therapeutically effective amount is fromabout 0.2 thru about 8 mg/person/dose.

14. A method of treating sexual disturbances according to enumeratedembodiment 13 where the sexually therapeutically effective amount isfrom about 0.5 thru about 5 mg/person/dose.

15. A method of treating sexual disturbances according to enumeratedembodiment 14 where the sexually therapeutically effective amount isfrom about 1 thru about 3 mg/person/dose.

16. A method of treating sexual disturbances according to enumeratedembodiment 1 where the compound of formula (A) is(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one.

17. A method of treating sexual disturbances according to enumeratedembodiment 16 where the compound of formula (A) is(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1).

18. A method of treating sexual disturbances according to enumeratedembodiment I where the pharmaceutically acceptable salt is selected fromthe group consisting of salts of the following acids methanesulfonic,hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic,citric, tartaric, fumaric, maleic, CH₃—(CH₂)_(n)—COOH where n is 0 thru4, HOOC—(CH₂)_(N)—COOH where n is as defined above.

19. A method of treating sexual disturbances according to enumeratedembodiment 1 where the compound of formula (A) is administered fromabout 10 minutes to about 8 hr prior to sexual activity.

20. A method of treating sexual disturbances according to enumeratedembodiment 19 where the compound of formula (A) is administered fromabout 0.5 hr to about 1 hr prior to sexual activity.

21. A method of treating sexual disturbances according to enumeratedembodiment 20 where the compound of formula (A) is administered about0.5 hr prior to sexual activity.

22. A method of treating sexual disturbances according to enumeratedembodiment 1 where the mammal does not have Parkinson's disease.

23. A method of treating sexual disturbances according to enumeratedembodiment 1 where the mammal does not experience postural hypotension.

24. A method of treating sexual disturbances according to enumeratedembodiment 1 where the compound of formula (A) is used in combinationwith a sexually effective amount of one or more vascular smooth musclerelaxation agents where both the compound of formula (A) is administeredwithin 8 hours prior to sexual activity and the vascular smooth musclerelaxation agent is administered to the human within a sexuallyeffective time period prior to sexual activity.

25. A method of treating sexual disturbances according to enumeratedembodiment 24 where the vascular smooth muscle relaxation agents isselected from the group consisting of phosphodiesterase type 5inhibitors, phosphodiesterase type 3 inhibitors, non-selectivephosphodiesterase inhibitors, nitric oxide donor drugs, alpha type 1adrenergic receptor antagonists, alpha type 2 adrenergic receptorantagonists, prostaglandin E1 receptor agonists (PGE1) and vasoactiveintestinal polypeptide (VIP) agents.

26. A method of treating sexual disturbances according to enumeratedembodiment 25 where the vascular smooth muscle relaxation agents isselected from the group consisting of sildenafil, ICOS-351, milrinone,papaverine, linsidomine, phentolamine, yohimbine, prostaglandin E1(PGE1) and VIP.

27. A method of inducing mating a non-human mammal which comprisesadministering a sexually mating amount of a compound of the formula (A)

where

R₁, R₂ and R₃ are the same or different and are:

—H,

C₁-C₆ alkyl,

C₃-C₅ alkenyl,

C₃-C₅ alkynyl,

C₃-C₅ cycloalkyl,

C₄-C₁₀ cycloalkyl,

phenyl substituted C₁-C₆ alkyl,

—NR₁R₂ where R₁ and R₂ are cyclized with the attached nitrogen atom toproduce pyrrolidiyl, piperidinyl, morphoninyl, 4-methyl piperazinyl orimidazolyl;

X is:

—H,

C₁-C₆ alkyl,

—F, —Cl, —Br, —I,

—OH,

C₁-C₆ alkoxy,

cyano,

carboxamide,

carboxyl,

(C₁-C₆ alkoxy)carbonyl,

A is:

CH,

CH₂,

CH-(halogen) where halogen is —F, —Cl, —Br, —I,

CHCH₃,

C═O,

C═S,

C—SCH₃,

C═NH,

C—NH₂,

C—NHCH₃,

C—NHCOOCH₃,

C—NHCN,

SO₂,

N;

B is:

CH₂,

CH,

CH-(halogen) where halogen is as defined above,

C═O,

N,

NH,

N—CH₃,

D is:

CH,

CH₂,

CH-(halogen) where halogen is as defined above,

C═O,

O,

N,

NH,

N—CH₃,

and n is 0 or 1, and where is a single or double bond, with theprovisos:

(1) that when n is 0, and

A is CH₂, CH-(halogen) where halogen is as defined above, CHCH₃, C═O,C═S, C═NH, SO₂,

then D is CH₂, CH-(halogen) where halogen is as defined above, C═O, O,NH, N—CH₃;

(2) that when n is 0, and

A is CH, C—SCH₃, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, N; then

D is CH, N;

(3) that when n is 1, and

A is CH₂, CH-(halogen) where halogen is as defined above, CHCH₃, C═O,C═S, C═NH, SO₂; and

B is CH₂, CH-(halogen) where halogen is as defined above, C═O, NH,N—CH₃; then

D is CH₂, C═O, O, NH, N—CH₃;

(4) that when n is 1, and

A is CH, C—SCH₃, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, N; and

B is CH, N; then

D is CH₂, C═O, O, NH, N—CH₃,

(5) that when n is 1, and

A is CH₂, CHCH₃, C═O, C═S, C═NH, SO₂, and

B is CH, N; then

D is CH, N; and pharmaceutically acceptable salts thereof.

28. A method of inducing mating according to enumerated embodiment 27where the non-human mammal is selected from the group consisting ofhorses, cattle, swine, sheep, transgenic mice, panda bears, elephants,zebras, lions, tigers, monkeys, apes, dogs and cats.

29. A method of inducing mating according to enumerated embodiment 27where the non-human mammal is a male.

30. A method of inducing mating according to enumerated embodiment 27where the non-human mammal is a female.

31. A method of inducing mating according to enumerated embodiment 27where the compound of formula (A) is administered orally, parenterallyand rectally.

32. A method of inducing mating according to enumerated embodiment 31where the compound of formula (A) is administered orally.

33. A method of inducing mating according to enumerated embodiment 27where the sexually mating amount is from about 0.003 thru about 0.2mg/kg/dose.

34. A method of inducing mating according to enumerated embodiment 33where the sexually mating amount is from about 0.01 thru about 0.125mg/kg/dose.

35. A method of inducing mating according to enumerated embodiment 27where the sexually mating amount is from about 0.025 thru about 0.075mg/kg/dose.

36. A method of inducing mating according to enumerated embodiment 27where the compound of formula (A) is(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one.

37. A method of inducing mating according to enumerated embodiment 36where the compound of formula (A) is(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1).

38. A method of inducing mating according to enumerated embodiment 27where the pharmaceutically acceptable salt is selected from the groupconsisting of salts of the following acids methanesulfonic,hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic,citric, tartaric, fumaric, maleic, CH₃—(CH₂)_(n)—COOH where n is 0 thru4, HOOC—(CH₂)_(N)—COOH where n is as defined above.

39. A method of inducing mating according to enumerated embodiment 27where the compound of formula (A) is administered from about 10 minutesto about 8 hr prior to mating.

40. A method of inducing mating according to enumerated embodiment 39where the compound of formula (A) is administered from about 10 minutesto about 1 hr prior to mating.

41. A method of inducing mating according to enumerated embodiment 40where the compound of formula (A) is administered from about 10 minutesto about 0.5 hr prior to mating.

42. A method of inducing mating according to enumerated embodiment 27where the compound of formula (A) is used in combination with a sexuallyeffective amount of one or more vascular smooth muscle relaxation agentswhere both the compound of formula (A) is administered within 8 hoursprior to sexual activity and the vascular smooth muscle relaxation agentis administered to the human within a sexually effective time periodprior to sexual activity.

43. A method of inducing mating according to enumerated embodiment 42where the vascular smooth muscle relaxation agents is selected from thegroup consisting of phosphodiesterase type 5 inhibitors,phosphodiesterase type 3 inhibitors, non-selective phosphodiesteraseinhibitors, nitric oxide donor drugs, alpha type 1 adrenergic receptorantagonists, alpha type 2 adrenergic receptor antagonists, prostaglandinE1 receptor agonists (PGE1) and vasoactive intestinal polypeptide (VIP)agents.

44. A method of inducing mating according to enumerated embodiment 43where the vascular smooth muscle relaxation agents is selected from thegroup consisting of sildenafil, ICOS-351, milrinone, papaverine,linsidomine, phentolamine, yohimbine, prostaglandin E1 (PGE1) and VIP.

45. A method of treating a sexual deficiency state in a human who hasepilepsy, craniopharyngioma, hypogonadism or who has had ahysterectomyoophorectomy, hysterectomy or oophorectomy which comprisesadministering a sexually therapeutically effective amount of a compoundof the formula (A)

where

R₁, R₂ and R₃ are the same or different and are:

—H,

C₁-C₆ alkyl,

C₃-C₅ alkenyl,

C₃-C₅ alkynyl,

C₃-C₅ cycloalkyl,

C₄-C₁₀ cycloalkyl,

phenyl substituted C₁-C₆ alkyl,

—NR₁R₂ where R₁ and R₂ are cyclized with the attached nitrogen atom toproduce pyrrolidiyl, piperidinyl, morphoninyl, 4-methyl piperazinyl orimidazolyl;

X is:

—H,

C₁-C₆ alkyl,

—F, —Cl, —Br, —I,

—OH,

C₁-C₆ alkoxy,

cyano,

carboxamide,

carboxyl,

(C₁-C₆ alkoxy)carbonyl,

A is:

CH,

CH₂,

CH-(halogen) where halogen is —F, —Cl, —Br, —I,

CHCH₃,

C═O,

C═S,

C—SCH₃,

C═NH,

C—NH₂,

C—NHCH₃,

C—NHCOOCH₃,

C—NHCN,

SO₂,

N;

B is:

CH₂,

CH,

CH-(halogen) where halogen is as defined above,

C═O,

N,

NH,

N—CH₃,

D is:

CH,

CH₂,

CH-(halogen) where halogen is as defined above,

C═O,

O,

N,

NH,

N—CH₃,

and n is 0 or 1, and where is a single or double bond, with theprovisos:

(1) that when n is 0, and

A is CH₂, CH-(halogen) where halogen is as defined above. CHCH₃, C═O.C═S, C═NH, SO₂,

then D is CH₂, CH-(halogen) where halogen is as defined above, C═O, O,NH, N—CH_(3,)

(2) that when n is 0, and

A is CH, C—SCH₃, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, N; then

D is CH, N,

(3) that when n is 1, and

A is CH₂, CH-(halogen) where halogen is as defined above, CHCH₃, C═O,C═S, C═NH, SO₂; and

B is CH₂, CH-(halogen) where halogen is as defined above, C═O, NH,N—CH₃; then

D is CH₂, C═O, O, NH, N—CH₃;

(4) that when n is 1, and

A is CH, C—SCH₃, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, N; and

B is CH, N; then

D is CH₂, C═O, O, NH, N—CH₃;

(5) that when n is 1, and

A is CH₂, CHCH₃, C═O, C═S, C═NH, SO₂, and

B is CH, N; then

D is CH, N; and pharmaceutically acceptable salts thereof to the human.

46. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the human is a male.

47. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the human is a female.

48. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the human has epilepsy.

49. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the human has craniopharyngioma.

50. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the human has hypogonadism.

51. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the human has had ahysterectomyoophorectomy.

52. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the human has had a hysterectomy.

53. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the human has a oophorectomy.

54. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the compound of formula (A) isadministered orally, intra-nasally, buccally, intra-pulmonary,parenterally and rectally.

55. A method of treating a sexual deficiency state according toenumerated embodiment 54 where the compound of formula (A) isadministered orally, intra-nasally, buccally and intra-pulmonary.

56. A method of treating a sexual deficiency state according toenumerated embodiment 55 where the compound of formula (A) isadministered orally.

57. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the sexually therapeutically effectiveamount is from about 0.2 thru about 8 mg/person/dose.

58. A method of treating a sexual deficiency state according toenumerated embodiment 57 where the sexually therapeutically effectiveamount is from about 0.5 thru about 5 mg/person/dose.

59. A method of treating a sexual deficiency state according toenumerated embodiment 58 where the sexually therapeutically effectiveamount is from about 1 thru about 3 mg/person/dose.

60. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the compound of formula (A) is(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one.

61. A method of treating a sexual deficiency state according toenumerated embodiment 60 where the compound of formula (A) is(SR)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1).

62. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the pharmaceutically acceptable salt isselected from the group consisting of salts of the following acidsmethanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric,nitric, benzoic, citric, tartaric, fumaric, maleic, CH₃—(CH₂)_(n)—COOHwhere n is 0 thru 4, HOOC—(CH₂)_(N)—COOH where n is as defined above.

63. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the compound of formula (A) isadministered from about 10 minutes to about 8 hr prior to sexualactivity.

64. A method of treating a sexual deficiency state according toenumerated embodiment 63 where the compound of formula (A) isadministered from about 0.5 hr to about 1 hr prior to sexual activity.

65. A method of treating a sexual deficiency state according toenumerated embodiment 64 where the compound of formula (A) isadministered about 0.5 hr prior to sexual activity.

66. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the mammal does not have Parkinson'sdisease.

67. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the mammal does not experience postural-1hypotension.

68. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the compound of formula (A) is used incombination with a sexually effective amount of one or more vascularsmooth muscle relaxation agents where both the compound of formula (A)is administered within 8 hours prior to sexual activity and the vascularsmooth muscle relaxation agent is administered to the human within asexually effective time period prior to sexual activity.

69. A method of treating a sexual deficiency state according toenumerated embodiment 68 where the vascular smooth muscle relaxationagents is selected from the group consisting of phosphodiesterase type 5inhibitors, phosphodiesterase type 3 inhibitors, non-selectivephosphodiesterase inhibitors, nitric oxide donor drugs, alpha type 1adrenergic receptor antagonists, alpha type 2 adrenergic receptorantagonists, prostaglandin E1 receptor agonists (PGE1) and vasoactiveintestinal polypeptide (VIP) agents.

70. A method of treating a sexual deficiency state according toenumerated embodiment 69 where the vascular smooth muscle relaxationagents is selected from the group consisting of sildenafil, ICOS-351,milrinone, papaverine, linsidomine, phentolamine, yohimbine,prostaglandin E1 (PGE1) and VIP.

71. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof which comprises administering a sexuallyuseful effective amount of a compound of the formula (A)

where

R₁, R₂ and R₃ are the same or different and are:

—H,

C₁-C₆ alkyl,

C₃-C₅ alkenyl,

C₃-C₅ alkynyl,

C₃-C₅ cycloalkyl,

C₄-C₁₀ cycloalkyl,

phenyl substituted C₁-C₆ alkyl,

—NR₁R₂ where R₁ and R₂ are cyclized with the attached nitrogen atom toproduce pyrrolidiyl, piperidinyl, morphoninyl, 4-methyl piperazinyl orimidazolyl;

X is:

—H,

C₁-C₆ alkyl,

—F, —Cl, —Br, —I,

—OH,

C₁-C₆ alkoxy,

cyano,

carboxamide,

carboxyl,

(C₁-C₆ alkoxy)carbonyl,

A is:

CH,

CH₂,

CH-(halogen) where halogen is —F, —Cl, —Br, —I,

CHCH₃,

C═O,

C═S,

C—SCH₃,

C═NH,

C—NH₂,

C—NHCH₃,

C—NHCOOCH₃,

C—NHCN,

SO₂,

N;

B is:

CH₂,

CH,

CH-(halogen) where halogen is as defined above,

C═O,

N,

NH,

N—CH₃,

D is:

CH,

CH₂,

CH-(halogen) where halogen is as defined above,

C═O,

O,

N,

NH,

N—CH₃;

and n is 0 or 1, and where is a single or double bond, with theprovisos:

(1) that when n is 0, and

A is CH₂, CH-(halogen) where halogen is as defined above, CHCH₃, C═O,C═S, C═NH, SO₂;

then D is CH₂, CH-(halogen) where halogen is as defined above, C═O, O,NH, N—CH₃;

(2) that when n is 0, and

A is CH, C—SCH₃, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, N; then

D is CH, N;

(3) that when n is 1, and

A is CH₂, CH-(halogen) where halogen is as defined above, CHCH₃, C═O,C═S, C═NH, SO₂; and

B is CH₂, CH-(halogen) where halogen is as defined above, C═O, NH,N—CH₃; then

D is CH₂, C═O, O, NH, N—CH₃;

(4) that when n is 1, and

A is CH, C—SCH₃, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, N; and

B is CH, N; then

D is CH₂, C═O, O, NH, N—CH_(3,)

(5) that when n is 1, and

A is CH₂, CHCH₃, C═O, C═S, C═NH, SO₂, and

B is CH, N; then

D is CH, N; and pharmaceutically acceptable salts thereof to the human.

72. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 71where the human is a male.

73. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 71where the human is a female.

74. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 71where the compound of formula (A) is administered orally, intra-nasally,buccally, intra-pulmonary, parenterally and rectally.

75. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 74where the compound of formula (A) is administered orally, intra-nasally,buccally and intra-pulmonary.

76. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 75where the compound of formula (A) is administered orally.

77. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 71where the sexually useful effective amount is from about 0.2 thru about8 mg/person/dose.

78. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 76where the sexually useful effective amount is from about 0.5 thru about5 mg/person/dose.

79. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 78where the sexually therapeutic amount is from about 1 thru about 3mg/person/dose.

80. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 71where the compound of formula (A) is(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one.

81. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 80where the compound of formula (A) is(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1).

82. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 71where the pharmaceutically acceptable salt is selected from the groupconsisting of salts of the following acids methanesulfonic,hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic,citric, tartaric, fumaric, maleic, CH₃—(CH₂)_(n)—COOH where n is 0 thru4, HOOC—(CH₂)_(N)—COOH where n is as defined above.

83. A method of increasing sexual desire, interest or performance in ahuman who is desirous according to enumerated embodiment 71 where thecompound of formula (A) is administered from about 10 minutes to about 8hr prior to sexual activity.

84. A method of increasing sexual desire, interest or performance in ahuman who is desirous according to enumerated embodiment 83 where thecompound of formula (A) is administered from about 0.5 hr to about 1 hrprior to sexual activity.

85. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 84where the compound of formula (A) is administered about 0.5 hr prior tosexual activity.

86. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 71where the mammal does not have Parkinson's disease.

87. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 71where the mammal does not experience postural hypotension.

88. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 71where the compound of formula (A) is used in combination with a sexuallyeffective amount of one or more vascular smooth muscle relaxation agentswhere both the compound of formula (A) is administered within 8 hoursprior to sexual activity and the vascular smooth muscle relaxation agentis administered to the human within a sexually effective time periodprior to sexual activity.

89. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 88where the vascular smooth muscle relaxation agents is selected from thegroup consisting of phosphodiesterase type 5 inhibitors,phosphodiesterase type 3 inhibitors, non-selective phosphodiesteraseinhibitors, nitric oxide donor drugs, alpha type 1 adrenergic receptorantagonists, alpha type 2 adrenergic receptor antagonists, prostaglandinE1 receptor agonists (PGE1) and vasoactive intestinal polypeptide (VIP)agents.

90. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 89where the vascular smooth muscle relaxation agents is selected from thegroup consisting of sildenafil, ICOS-351, milrinone, papaverine,linsidomine, phentolamine, yohimbine, prostaglandin E1 (PGE1) and VIP.

91.(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thioneand pharmaceutically acceptable salts thereof.

92. A compound according to enumerated embodiment 91 which is(5R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione malate.

93. A method of treating sexual disturbances according to enumeratedembodiment I where the compound of formula (A) is(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione.

94. A method of inducing mating according to enumerated embodiment 27where the compound of formula (A) is(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione.

95. A method of treating a sexual deficiency state according toenumerated embodiment 45 where the compound of formula (A) is(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione.

96. A method of increasing sexual desire, interest or performance in ahuman who is desirous thereof according to enumerated embodiment 71where the compound of formula (A) is(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione.

What is claimed is:
 1. A method of inducing mating in a non-human mammalwhich comprises orally administering a sexually mating amount rangingfrom about 0.003 thru about 0.2 mg/kg/dose per day of a compoundselected from the group consisting of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1,-ij]quinolin-2(1H)-one,(5R)-5-methylamino-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione,and pharmaceutical acceptable salts thereof to the non-human mammal. 2.The method according to claim 1 where the non-human mammal is selectedfrom the group consisting of horses, cattle, swine, sheep, transgenicmice, panda bears, elephants, zebras, lions, tigers, monkeys, apes,dogs, and cats.
 3. The method according to claim 1 where the non-humanmammal is a male.
 4. The method according to claim 1 where the non-humanmammal is a female.
 5. The method according to claim 1 where thesexually mating amount is from about 0.01 thru about 0.125 mg/kg/dose.6. The method accroding to claim 5 where the sexually mating amount isfrom about 0.025 thru about 0.075 mg/kg/dose.
 7. The method according toclaim 1 where the pharmaceutically acceptable salt is(5R)-methylamino)5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate (1:1).
 8. The method according to claim 1 where thepharmaceutically acceptable salt is selected from the group consistingof salts of the following acids: methanesulfonic, hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric,fumaric, maleic, CH₃—(CH₂)_(n)—COOH where n is 0 thru 4, andHOOC—(CH₂)_(n)—COOH where n is as as defined above.
 9. The methodaccording to claim 1 where the compound or pharmaceutically acceptablesalt is administered from about 10 minutes to about 8 hr prior tomating.
 10. The method according to claim 9 where the compound orpharmaceutically acceptable salt is adminsitered from about 10 minutesto about 1 hr prior to mating.
 11. The method according to claim 10where the compound or pharmaceutically acceptable salt is administeredfrom about 10 minutes to about 0.5 hr prior to mating.
 12. The methodaccording to claim 1 where the compound or pharmaceutically acceptablesalt is used in combination with a sexually effective amount of one ormore vascular smooth muscle relaxation agents where the compound orpharmaceutically acceptable salt is administered within 8 hours prior tomating and the vascular smooth muscle relaxation agent is administeredwithin a sexually effective time period prior to mating.
 13. The methodaccording to claim 12 where the vascular smooth muscle relaxation agentis selected from the group consisting of phosphodiesterase 5 inhibitors,phosphodiesterase type 3 inhibitors, non-selective phosphodiesteraseinhibitors, nitric oxide donor drugs, alpha type 1 adrenergic receptorantagonists, alpha type 2 adrenergic receptor antagonists, E1 receptoragonists, and vasoactive intestinal polypeptide agents.
 14. The methodaccording to claim 13 where the vascular smooth muscle relaxation agentis selected from the group consisting of sildenafil, tadalafil,milrinone, papaverine, linsidomine, phentolamine, yohimbine,prostaglandin E1 receptor agonists, and vasoactive intestinalpolypeptide agents.
 15. The method according to claim 1 where thepharmaceutically acceptable salt is(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionemaleate.